DESCRIPTION(provided by applicant): Diet, especially a high-fat diet, is of great concern to Americans for it has far-reaching effects on their health and well being. Obesity is a major health factor that affects the body's susceptibility to a variety of diseases such as heart attack, stroke, and diabetes. Obesity is a measure of the fat deposited in the adipose in consequence to food intake, fatty acid and triglyceride synthesis and fatty acid oxidation and energy consumption. Excess food provides not only the timely energy needs of the body, but promotes glycogen synthesis and storage in liver and muscle and fatty acid and triglyceride synthesis and storage in the fat tissues. Calorie restriction or starvation promotes glycogenolysis that supplies glucose where needed and lipolysis that supplies fatty acids for oxidation and energy production. Insulin and glucagon are the hormones that coordinate these processes. Malonyl-CoA, the key intermediate in fatty acid synthesis, has recently assumed an additional role as a second messenger that regulates energy levels (ATP) through fatty acid oxidation, which in turn affects fatty acid synthesis and carbohydrate metabolism. The acetyl-CoA carboxylases, ACC1 and ACC2, catalyze malonyl-CoA synthesis, through the carboxylation of acetyl-C0A, the product of pyruvate dehydrogenase. Hence, studies of the carboxylases interrelate three major metabolic pathways-carbohydrate metabolism, fatty acid synthesis, and fatty acid oxidation. The differential expression of ACC1 and ACC2 in various tissues suggests that they may have differential functions. We showed that ACC2 is associated with the mitochondria, and through its product malonyl-CoA, it may be involved in the regulation of fatty acid oxidation. ACC 1 is localized in the cytosol and generates malonyl-C0A for the synthesis of fatty acids. Results from knockout mouse models of ACC 1 and ACC2 support the hypothesis that ACC1 and ACC2 play distinct and different roles in animal physiology and energy metabolism. A mutation in ACC1 led to embryonic lethality. Acc2-/- mutant mice had normal life span, higher fatty acid oxidation rate, and accumulated less fat in their livers and adipose tissues than the wild-type mice fed the same normal diet. We plan to study the biochemical and physiological implications of these observations as they relate to our understanding of the hormonal and dietary regulation of fatty acid metabolism in normal and disease states, especially those of diabetes and obesity.